| Project/Area Number |
21791000
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pediatrics
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
IMAMURA Toshihiko Kyoto Prefectural University of Medicine, 医学研究科, 助教 (30444996)
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| Project Period (FY) |
2009 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 小児血液学 / MLL / AF4 / 白血病発症機序 / レトロウイルス / 乳児白血病 |
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| Research Abstract |
Because the prognosis of MLL-AF4-positive acute lymphoblastic leukemia is still extremely poor, understanding of leukemogenic mechanism of MLL-Af4 fusion gene is important for the development of new treatments. We analyzed the leukemogenic mechanism of MLL-AF4 fusion gene using retroviral gene expression system. As a result of myeloid transformation assay, we revealed that MLL-murine Af4 (mAf4) could immortalize murine linenage-depleted bone marrow (Lin-BM) cells. Using a series of hybrid mutants of human AF4/mAf4, we found that amino acids 1026 to 1177 of mAf4 are essential for the leukemogenesis of MLL-mAf4 fusion gene. Overexpression of HoxA9, A10, and Meis1 was confirmed by quantitative RT-PCR analysis of the transduced Lin-BM cells. Chromatin immunoprecipitation (ChIP) assay demonstrated histone H3 lysine79 (H3K79) dimethylation was occurred in promoter regions of HoxA9. Based on these results, we considered that MLL-mAf4 immortalized murine Lin-BM cells by induction of the overexpression of HoxA genes through H3K79 dimethylation in promoter regions of these genes. Our mouse model expressing MLL-mAf4 reproduces well the leukemogenic mechanism of human MLL-AF4-positive leukemias, it is expected to be a good model for the development of new treatments.
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